GENETICS IN HEREDITARY NEUROPATHY

ERNESTO ALONSO, SWETHA JASTI,MAZEN M.DIMACHKIE, RICHARD J. BAROHN, MELANIE GLENN, OMAR JAWDAT, JEFFREY STATLAND, LAURA HERBELIN, CONSTANTINE FARMAKIDIS,DUAA JABARI, MAMATHA PASNOOR

40 ANNUAL CARELL-KRUSSEN NEUROMUSCULAR SYMPOSIUM, DALLAS, TEXAS FEBRUARY 23, 2018 Background Hereditary neuropathies are a large group of genetically and phenotypically heterogeneous disorders, categorized by involvement of motor, sensory and or autonomic nerves ( Dyck, 2005) Divided in 3 categories ◦Hereditary motor and sensory neuropathies (HMSN) also known CMT ◦Hereditary motor neuropathies (HMN) ◦Hereditary sensory and autonomic neuropathies (HSAN) Diagnosis is established based on history and clinical assessment About seventy genes have been described in the literature to cause inherited neuropathies (Rossor, 2013) Inheritance : autosomal dominant, autosomal recessive, X-linked inheritance patterns, sporadic Background

A genetic diagnosis is identified in ◦ 50-70% of Charcot-Marie-Tooth disease (Vallat , 2013) patients ◦ 30% of hereditary sensory and autonomic neuropathy (HSAN) (Rotthier, 2012) ◦ 20% of distal motor neuropathy (Rossor, 2012)

With increasing availability of genetic testing new mutations are being identified with associated clinical phenotypes ◦ PMP22 deletions cause 80 % of HNPP cases ◦ PMP22 duplications cause 70 % of CMT 1 cases ◦ Pathogenic mutations in some genes have been associated with multiple phenotypes or clinical patterns ( eg mutations in GARS gene can be associated with Charcot-MarieTooth type 2D or with distal SMA type V) Objectives /Study Design

•Objective • To review the genetic mutations identified in patients with suspected hereditary neuropathy at KUMC • Associate with the clinical phenotypes

• Study Design: Retrospective chart review Methods • IRB approval for exempt status was obtained •A retrospective chart review was performed of patients with suspected hereditary neuropathy with genetic testing performed between January 2013 to December 2017 •100 charts were reviewed to date •Information was collected on the demographics, clinical findings, laboratory data, electro diagnostic testing and genetic testing results •Data obtained based on available free genetic testing through Alynlam Results

•Total number of charts reviewed: 100 •Demographics: • Mean Age : 57.91 ± 14.95 • Gender: Male 57, Female 43 • Positive family history: 25 Results SYMPTOMS

PAIN 61% AUTONOMIC 9%

SENSORY-MOTOR 51% SENSORY 40% MOTOR 5%

EDX Axonal Demyelinating Sensory only 6 3

Motor only 5 2

Signs #of patients Sensorimotor 41 12 No large fiber neuropathy : 31 patients Results: Genetic testing Genetic Test results Positive: 9 9%

1-Positive Negative: 41 50% 41% 2-Negative Variants of unknown significance: 50 3-VUSI

Positive: POSITIVE GENETIC TESTS ◦ PMP 22 duplication: 3 PMP22 ◦ PMP 22 deletion: 6 Duplication 3/33% PMP22 Deletion 6/66% Results/VUS

Total number of mutations seen :42 mutations Type of inheritance: More than one mutation seen in :27(64%) AD 25(59.5%) One mutation: 15(36%) AR 15(35.7%) X-linked: 2(4.8%) Most common mutations seen: PRX( 5/12%)

Number of Heterozygo Dominant vs Other Associated gene (no Number of Heterozygou Dominant vs Other Associated gene (no Variant Gene patients us recessive patients ) Variant Genea patients s recessive patients ) MED25 2 yes AR no DST 2 yes AR EGR2, SETX; FBX038 ATP,7A, GJB1, LAS1L, PDK3, PRPS1, AARS 3 yes AR LMNA AIFM1 1 yes X-link UBA1 TRPV4 3 yes AD CHCHD10 ;SCN10A, WNK1 PLEKHG5 1 yes AR no IGHMBP2 2 yes AR no FBX028 2 yes AD DST ALMS1 1 yes AR no IKBKAP 2 yes AR SCN10A, SPTLCZ COL6A1 1 yes AR no SBF2 1 yes AD no VRK1 1 yes AR no GJV1 1 yes X-link LRSAM1 SYNE2 1 yes AR no SCN11A 1 yes AD SCN9A KIF1A 2 yes AR no TXNRD2 1 yes AR no MATR3 1 yes AD SELENON SETX 4 yes AR DST, EGR2; PRX; DCTN1 GARS 2 yes AD no CHCHD10 1 yes AD TRPV4 FLNC 1 yes AD VCL CLCN1 1 yes AD FLNC REEP1 1 yes AR no INF2 1 yes AR no DCTN1 2 yes AD FB038, SPG11; SETX ATL1 1 yes AD SH3TC2 CPT1C 2 yes AR no SLC52A2 1 yes AR DYNC1H1 SPTLC1 1 yes AD no SH3TC2 1 yes AR ATL1 LRSAM1 1 yes AD GJV1 LMNA 1 yes AR AARS SPTLCZ 1 yes AD IKBKAP, SCN10A PRX 5 yes AR SETX ; SCN11A; WNK1 EGR2 1 yes AR DST, SETX DYNC1H1 2 yes AD SLC52A2; SCN11A SPG11 1 yes AR DCTN1, FB038 IKBKAP, SPTLCZ ; TRPV4, VCL 1 yes AD/AR FLNC SCN10A 3 yes AD WNK1 SELENON 1 yes MATR3 Results

Positive (n=9) VUS (n=50) Negative(n=41) Age 100 90 80 Age 49±13.6 65±14.3 58.6±18.1 70 60 50 Positive 40 VUS Age(years) Gender 30 Negative 20 10 0 Male 5 (56%) 27(54%) 25(61%) 0 20 40 60 Patients

Female 4(44%) 23(46%) 16(39%)

Family history 6(66%) 9(18%) 10(24%) Results Positive (n=9) VUS (n=50) Negative ( n=41) Pain 8(88%) 32(64%) 22 (54%) Sensory 9 (100%) 45(90%) 37(90%) Motor weakness 8(88%) 35(70%) 21(51%) Foot deformities 6(66%) 14(28%) 22(54%) Foot drop 3(33%) 8(16%) 6(14.6%) CK elevation 3/7(43%) 14/32(44%) 9/20(45%) EDX testing Demyelinating 3(33%) 7(14%) 6(15%) Axonal 6(66%) 25(50%) 21(51%) Normal 0 16(32%) 14(34%) DISCUSSION 1) PMP22 Deletions comprise 80% of the patients with hereditary neuropathy with pressure palsies and PMP22 Duplications comprise 70% of the patients with CMT 66% of our patients with positive test had PMP22 deletions and 33% had PMP22 duplications. PMP22 gene mutation is most common in our group of positive patients 2) Unlike prior conception of no pain in hereditary neuropathy, pain reported in 74% patients with HNPP (Beales, 2017) and in CMT frequency ranges between 56 to 96% (Na Young Jeong, 2013) 88% of our patients with positive genetic testing and 64% with VUS reported pain 3) Sensory symptoms are usually mild and usually distal sensory loss is mostly reported in adults, more common in hereditary sensory neuropathies Sensory symptoms have been reported by most of our patients and all with positive genetic test result DISCUSSION 4) Foot deformities become more prevalent with age but are variable even among same-age relatives (Dyck and Lambert 1968) 66% of our patients with positive result had foot deformities 5) Since the early 1990s, over 75 genes have been found to be defective in Charcot-Marie-Tooth disease patients 6) PRX gene encodes L- and S-periaxin, proteins of myelinating Schwann cells, and is mutated in Dejerine-Sottas syndrome (MIM 145900) and Charcot-Marie-Tooth disease type 4F PRX has been the most common identified mutation in our variants of unknown significance and not associated with any particular phenotype Conclusion

1) Genetic testing has been positive in only 9% of patients, however variants of unknown significance have been present in 50% of our patients 2) Pain is a prominent feature in most of our patients 3) Foot deformities are common in patients with positive genetic testing, less common in our VUS group 4) No specific phenotype could be identified within the VUS group, probably due to the wide variability and small numbers of each gene mutation identified Questions & Discussion

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